MAXIMAL PROLIFERATION OF CYTOTOXIC T-LYMPHOCYTES REQUIRES REVERSE SIGNALING THROUGH FAS LIGAND

Fas ligand (FasL/CD95L) is best known for its role in delivering apopt otic signals through its receptor, Fas (APO-1/CD95). In this study, we present evidence that Fast has a second role as a signaling receptor. Alloantigen-specific proliferation by multiple Fast-murine CTL lines is depressed compared to that of FasL(+) CTL lines. Fast(-) CTLs kill efficiently on a per recovered cell basis and can achieve wild-type le vels of proliferation upon stimulation by optimal doses of anti-CD3, s uggesting the lack of a costimulatory signal during antigen stimulatio n. To test this hypothesis directly, soluble FasIgG, a fusion protein of murine Fas and human IgG(1), was added to FasL(+) CTLs to demonstra te that blocking cell surface Fas-FasL interactions mimics the depress ion observed for Fast(-) CTLs. In addition, plate-bound FasIgG in conj unction with suboptimal anti-CD3 stimulation augments proliferative si gnals in FasL(+) but not Fast(-) CTLs. In contrast to these results wi th CD8(+) T cells, alloantigen-stimulated FasL(-) CD4(+) T cells proli ferate vigorously compared to FasL(+) cells. These data demonstrate th at reverse signaling through Fast is required for CTLs to achieve maxi mal proliferation and may provide clues to differences in the homeosta tic regulation of activated CD4(+) and CD8(+) T cells during an immune response.